Swaby Lindsay G, Sauber Faith L, Miller Madelyn H, Xavier Mylena C, Lim Wesley, Poulson Peter Daniel, Zhu Xiang, Zhang Bin, Tigno-Aranjuez Justine T
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States.
Immunity and Pathogenesis Division, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States.
J Immunol. 2025 Jun 15. doi: 10.1093/jimmun/vkaf126.
Allergic asthma is a chronic inflammatory disease of the airways characterized by a type 2-high adaptive immune response towards common aeroantigens such as dust mite, pollen, and animal dander. Despite the advances made toward translation of various biologics into the clinic, the limited efficacy of these therapies in certain populations, combined with the ineligibility of some patients for treatment (clinically or economically), have led to the continued need for the development of more widely effective allergic asthma therapies. Our lab previously identified lectin mannose-binding 1 (LMAN1) as a novel receptor for house dust mite (HDM) and showed that in vitro, LMAN1 downregulated inflammatory NF-κB signaling in DCs in response to HDM. In this follow-up work, we investigated the in vivo relevance of LMAN1 by subjecting LMAN1 knockout (KO) mice and wild type (WT) littermate controls to a model of HDM-induced allergic asthma. Surprisingly, we discovered that loss of LMAN1 led to opposing effects on airway hyperresponsiveness (AHR), which were dependent on the sex of the mice. HDM-treated female LMAN1 KO mice showed increased AHR, while HDM-treated male KO mice showed decreased AHR, compared with their WT counterparts. We further identified the features of HDM-induced asthma which may account for the gender-biased effects of LMAN1 on lung function. This work not only highlights the complexity of the loss of LMAN1 in vivo but also suggests that such sex-dependent responses should be taken into consideration when pursuing LMAN1 as a therapeutic target for treatment of allergic asthma.
过敏性哮喘是一种气道慢性炎症性疾病，其特征是对常见气传抗原（如尘螨、花粉和动物皮屑）产生2型高适应性免疫反应。尽管在将各种生物制剂转化为临床应用方面取得了进展，但这些疗法在某些人群中的疗效有限，再加上一些患者不符合治疗条件（临床或经济方面），导致持续需要开发更广泛有效的过敏性哮喘治疗方法。我们实验室之前鉴定出凝集素甘露糖结合蛋白1（LMAN1）是屋尘螨（HDM）的一种新型受体，并表明在体外，LMAN1可下调树突状细胞（DC）中对HDM产生反应的炎症性核因子κB信号通路。在这项后续工作中，我们通过将LMAN1基因敲除（KO）小鼠和野生型（WT）同窝对照小鼠置于HDM诱导的过敏性哮喘模型中，研究了LMAN1在体内的相关性。令人惊讶的是，我们发现LMAN1的缺失对气道高反应性（AHR）产生了相反的影响，这取决于小鼠的性别。与野生型对照相比，经HDM处理的雌性LMAN1 KO小鼠的AHR增加，而经HDM处理的雄性KO小鼠的AHR降低。我们进一步确定了HDM诱导哮喘的特征，这些特征可能解释了LMAN1对肺功能的性别偏向性影响。这项工作不仅突出了LMAN1在体内缺失的复杂性，还表明在将LMAN1作为过敏性哮喘治疗的靶点时，应考虑这种性别依赖性反应。
